Brain Injury Model Created to Find New Medication

The experiments on the fish were conducted non-invasively, using a laser machine.
Photo credit: Danil Lomovskikh

Scientists from Russia and Taiwan (China) have developed and successfully tested a new model of traumatic brain injury (TBI) in zebradanio fish (Danio rerio). The method is based on irradiating the brains of adult individuals of these popular aquarium and laboratory fish with a unique laser system with precise aiming, which was specially developed by scientists. The application of this model allowed the researchers to simulate the TBI and identify molecular targets promising for the treatment of neurotrauma and its consequences. This paves the way for preclinical zebrafish testing of new neuroprotective medications.

The work was financially supported by the Russian Science Foundation (grant № 20-65-46006). An article describing the research was published in the highly rated scientific journal Pharmaceutics. The subject of the research was explained by Alan Kaluev, professor of the Russian Academy of Sciences, member of the European Academy, leading researcher of the Research Institute of Neuroscience and Medicine, professor of the St. Petersburg State University and Sirius Scientific-Technological University, leading researchers of the Ural Federal University and the Moscow Institute of Physics and Technology. Professor Kaluev is a leading scientist within the framework of research conducted at the Scientific Novosibirsk Research Institute of Neuroscience and Medicine (laboratory of Tamara Amstislavskaya and Maria Tikhonova).

The most common experimental models of brain injury in both rodents and zebrafish, such as mechanical blows to the head or needle piercing of the brain, involve penetrating brain tissue damage. However, these models do not correctly reproduce TBI. In the created model, due to the fact that the skin and skull of the used zebradanio species are transparent, it was possible to hit directly the brain, and non-invasively.

"Moreover, in this work the localization, power and duration of the laser irradiation have been carefully adjusted and optimized. Our method allows a targeted effect on the fish brain, despite its small size, making all undesirable damage excluded. The superficial tissues of the body were not exposed to destructive effects, and no fish died as a result of irradiation," explains study co-author Alan Kaluev.

In 10 minutes after the laser irradiation, the fish regained consciousness. However, in the first two days, the irradiated zebradanios moved much less actively: less frequently, more slowly, covering shorter distances, more often and for a long time frozen in place, noticeably less in the upper part of the aquarium than the uninjured individuals from the control group. This was indicative of serious disturbances in the normal behavior of the fish with TBI. At the same time, even on the seventh day, the motor activity of the irradiated fish was lower than that of the unirradiated ones. And the fact that their reactions strikingly accurately reproduced the behavior of mammals and humans with TBI indicated the validity of the developed model.

At the same time, by analyzing several molecular biomarkers of neuroinflammation, neuronal damage and repair, scientists were convinced that, unlike mammals, these zebrafish are capable of full recovery of brain function as early as one week after neurotrauma. Therefore, they may be particularly interesting for identifying and studying the mechanisms of neuroregeneration and for preclinical testing of appropriate medications.

"We evaluated several potential molecular targets to identify therapeutic mechanisms for brain injuries and their consequences. The results obtained showed that, first, throughout the observation period, microglia, cells of the central nervous system that both eliminate cellular debris and other harmful factors and trigger regenerative processes, were activated in the zebradanio brain. Apparently, microglia activation plays an important role in the body's response to primary brain injury in its acute phase. At the same time, prolonged and excessive activation of microglia may cause further brain damage. Thus, regulation of microglia activity may represent a promising approach in the therapy of craniocerebral injuries," notes Alan Kaluev.

Secondly, one of the biomarkers - the brain neurotrophin protein BDNF, which supports the reproduction, survival and development of neurons - attracted special attention of scientists. Having significantly decreased immediately after zebradanio irradiation, the expression of BDNF abruptly equaled the values of the fish from the control group also on the seventh day.

"We believe that BDNF contributes to the survival and full functional recovery of damaged brain tissue in this new model of brain injury. Thus, this protein, as well as its analogues, may have a special therapeutic potential in craniocerebral trauma," commented the scientist.

The studies conducted and the results achieved are of great practical importance, since neurotraumas annually affect about 60 million people in the world, often leading to hospitalization, disability, and death. These injuries are most often caused by shocks, blows, falls, and penetrating head wounds, such as those resulting from sports activities, traffic accidents, or assaults. Importantly, head injuries can predispose to serious neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Yet, it is mild domestic brain injuries that are the most common type of neurotrauma and require both in-depth study at the molecular, cellular, and behavioral levels and new, productive therapies.

Source/Credit: Ural Federal University

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